In recent years, the demand for various biocompatible materials has been increased for use in, for example, tissue engineering and drug delivery systems (DDSs). For example, a method for suppressing side effects and improving retention in the blood by modifying a physiologically active substance such as a drug or polypeptide with a hydrophilic polymer such as polyethylene glycol has been studied. Furthermore, a cross-linked polymer composition formed through gelation of a plurality of components has been developed and studied for use in, for example, cell scaffolds, drug-release devices, sutures/bone fixation agents, hemostatics, and tissue adhesion inhibitors.
An example of such a cross-linked polymer composition is a hydrogel formed by mixing a synthetic polypeptide or a polyethylene glycol derivative having a plurality of nucleophilic groups such as a primary amino group and a thiol group and a hydrophilic or hydrophobic polymer derivative having an electrophilic group such as an N-hydroxysuccinimidyl group.
To sufficiently exhibit the function of the gel formed of a cross-linked polymer, the polymer derivatives to be mixed equally react with each other and a three-dimensional network structure needs to be uniformly formed. Therefore, it is important to introduce a reactive functional group into the polymers at a high introduction ratio.
Furthermore, biodegradable polymers such as polylactic acid and polyglycolic acid and copolymers obtained by introducing such biodegradable polymers into polyethylene glycol or the like as biodegradable moieties have received attention and have been widely used in order to enzymatically or non-enzymatically hydrolyze a drug, which has been implanted into a body or sustainedly released at a target site, into nontoxic components and cause metabolism and absorption.
It is highly important to establish a method for production of a high-purity polymer derivative on an industrial scale, the polymer derivative being produced by introducing a reactive functional group into such a polymer having a biodegradable moiety.
One of methods for production of a high-purity polymer derivative having a biodegradable moiety is purification performed by preparative liquid chromatography. However, polymer derivatives having different numbers of functional groups have similar physical properties depending on their structures. Therefore, it is often difficult to separate a target substance or conduct removal. Even if removal can be conducted, some problems such as a decrease in the yield are caused. Thus, such a method is not efficient on an industrial scale. Although a polymer derivative can be produced with a high yield by purification performed by recrystallization or crystal precipitation, it is also difficult to remove polymer derivatives having different numbers of functional groups.
Accordingly, in order to produce a high-purity polymer derivative having a biodegradable moiety on an industrial scale, it is important to achieve a high functional group introduction ratio in a reaction process.
For example, PTL 1 discloses, as a method for production of a polymer derivative having a biodegradable moiety, a method for production of acrylic-polyhydroxy acid-polyoxyethylene obtained by causing polyhydroxy acid-polyoxyethylene to react with acryloyl chloride in the presence of triethylamine. However, triethylamine hydrochloride formed as a by-product is filtered at a very low rate, and cools and solidifies on a filter surface. Consequently, the filtration cannot be completed. From this point of view, the method disclosed in PTL 1 is not suitable for industrial production.
In the reaction of introducing a functional group, if the type of catalyst is inappropriate, the bond of the biodegradable moiety is cleaved. Thus, the selection of the catalyst is limited. In particular, a substance terminated with a secondary hydroxyl group, such as polylactic acid, has reactivity lower than that of a substance terminated with a primary hydroxyl group. Therefore, the selection of a catalyst is particularly important to produce a high-purity polymer.
PTL 2 discloses a method for production of pentaerythritol polyoxyethylene-polylactide-tetraglutarate obtained by causing pentaerythritol polyoxyethylene-polylactide terminated with a secondary hydroxyl group to react with glutaric anhydride in the presence of potassium carbonate.